Nervous signaling includes an electrical and a chemical component

Nervous signaling is long distance – information travels from the signaling neuron cell body (soma) to some target cell, which can be milimeters to meters away. The signaling neuron “reaches out” to the target cell with a long, skinny appendage called the axon. The axon ends at the axon terminus. The axon terminus forms a special junction with the target cell called a synapse. The axon can be milimeters to about one meter long. The distance across the synapse (the synaptic cleft) is only about 20 - 50 nm. Information travels from the cell body to the axon terminus as an electrical current called an action potential. Actional potentials travel or propagate along a membrane. Information travels across the synaptic cleft as a chemical signaling molecule, which is known as a neurotransmitter.

Excitable membranes enable the generation and propogation of action potentials

Excitability is the ability of a membrane to generate and propogate an action potential. A neuron is an excitable cell (muscle cells and beta cells of the pancreas are also excitable). Only the membrane of the axon is excitable – this is important. What makes the axon membrane excitable is the dense expression of voltage-gated Na+ channels – this is also important. An excitable membrane (or cell) that is not excited is resting.

Cell membranes have a difference in charge across the membrane that creates a membrane potential.

Cells (all cells!) use pumps (such as the Na+/K+ pump) to concentrate some ions in the cytosol and others in the interstitial fluid. The consequence of this is an assymetric distribution of charges across the membrane – the inside of the membrane is relatively negatively charged and the outside of the membrane is relatively positively charged. The charge on each side of the membrane is called an electrical potential. The difference in electrial potential across the membrane is an electrial potential difference or voltage. This electrical potential difference (= voltage) across the membrane is known as the membrane potential. An electrical potential difference is a kind of potential energy – it is a kind of stored energy that can be used to do stuff (“do work”). Cells use membrane potentials to do stuff.

A neuron has a resting membrane potential

The voltage across a resting neuron membrane is about -70 milivolts (mV). The minus is kind of arbitrary – physiologists use the sign to indicate the charge inside the membrane relative to outside the membrane. Since the inside is relatively negative in a resting membrane, we say the voltage is -70 mV. This voltage is small relative to the voltages that we are used in our batteries and houses, which range from a few volts (like a 9 V battery) to hundreds of volts (the outlets in our house are 120 V).

The resting membrane potential is the resting potential. It occurs because of an equilibrium in total charge crossing the membrane. Most of the charges crossing the membrane are due to ion pumps but there are ion leak channels – these are called leak channels because they are not gated, they are always open. In general, there is a low density of leak channels so resting neuron membranes are not very permeable to the major ions Na+, K+, Cl-, Ca++. By “equilibrium in total charge” I mean charge only, so ignoring the element (Na or K or Cl). In a resting neuron membrane, each of the individual ions is not at equilibrium, meaning there is diffusion of these ions down their gradients through these leak channels but this diffusion is minor because (importantly!) membranes have a low density of leak channels.

For the resting neuron membrane, we say the membrane is polarized. The root “polar” is used to refer to anything with some directional axis (polar covalent bonds, polarized organization in epithelial cells, etc.)

Stimulation of a neuron generates an action potential at the axon hillock/initial segment (the junction of the soma and axon) that travels (propagates) to the axon terminus

An action potential is a particular pattern of change in membrane potential over time – this is a wierd use of the word “potential”. In the action potential, the membrane rapidly depolarizes (gets less negative/more positive) and then rapidly repolarizes (gets more negative/less positive) before returning to the resting potential.

The rising part of the action potential is the depolarization phase. The falling part of the action potential is the repolarization phase. The part of the action potential where the membrane potential is more negative than the resting potential is the hyperpolarization phase. To understand the mechanism of the action potential, and what processes create these phases, we need to talk about the diffusion of ions.

Ion diffusion is determined by the electrochemical gradient of the ion

Because ions are charged particles, and charged particles are attracted/repelled by other charged particles, the direction and magnitude of ion diffusion is a function of both the chemical gradient specific to the ion and the electrical gradient. The chemical gradient is the difference in the ion’s concentration on each side of the membrane. The electrical gradient is a function of the ion’s charge (but not which ion it is) and the electrical potential difference across the membrane. These two gradients add – the sum is the electrochemical gradient.

Understand how vectors add.

In a resting cell membrane, the electrical and chemical gradients for Na+ are both large and in the same direction, so the electrochemical gradient is huge.

Because of the Na+/K+ pump, the chemical gradient for Na+ is directed inward and is large. In a resting neuron membrane, the inside of the membrane is negative relative to the outside – Na+ ions are attracted to the inside and repelled by the outside – so the electrical gradient is directed inward and is large. These two gradients are in the same direction and both are large so the electrochemical gradient is directed inside and is really large.

In a resting cell membrane, the electrical and chemical gradients for K+ are both large but in opposite directions but the chemical gradient is a bit bigger than the electrical, so the electrochemical gradient is directed outward and is small.

Because of the Na+/K+ pump, the chemical gradient for K+ is directed inward and is really large (bigger than that of Na+). In a resting neuron membrane, the inside of the membrane is negative relative to the outside – K+ ions are attracted to the inside and repelled by the outside – so the electrical gradient is directed inward and is large (this gradient is the same as that for Na+ because they are both + charged ions). These two gradients are in opposite directions and both are large but the chemical gradient is a little larger than the electrical, so the electrochemical gradient is directed outside but is small.

Ions have an equilibrium potential

\(\textrm{E}_\textrm{ion}\) is the equilibrium potential of an ion. The equilibrium potential (also called the Nernst potential) of an ion is the membrane potential at which the ion is at equilibrium – there is no electrochemical gradient, which occurs when the chemical and electrical gradients are equal in magnitude but have opposite directions, so they add to zero. At the equilibrium potential, if the membrane were suddenly permeable to the ion, there would be no diffusion of the ion. If a membrane is not at the ion’s equilibrium potential, then, if the membrane is suddenly made permeable to the ion, the ion will diffuse down the ion’s electrochemical gradient until equilibrium is reached. This electrical current across the membrane (created by moving charges) drives the membrane potential to the ion’s equilibrium potential. We can use this concept to understand the direction and magnitude of ion currents across a membrane due to diffusion of the ion down it’s electrochemical gradient.

The \(\textrm{E}_{\textrm{Na}^+}\) is +50 mV

The \(\textrm{E}_{\textrm{Na}^+}\) depends on the neuron but it is usally around +50 to +60 mV. A resting potential of -70 mV is far from \(\textrm{E}_{\textrm{Na}^+}\), so the initial rate of diffusion of Na+ (if the membrane is suddenly made permeable to Na+) is fast. This rate will decrease as the system goes to equilibrium. We know that the Na+ current is inward, because Na+ is positively charged and an inward current of positive charges makes the membrane less negative/more positive.

The \(\textrm{E}_{\textrm{K}^+}\) is -100 mV

The \(\textrm{E}_{\textrm{K}^+}\) depends on the neuron but it is usally around -90 to -100 mV. A resting potential of -70 mV is pretty close to \(\textrm{E}_{\textrm{K}^+}\), so the initial rate of diffusion of K+ (if the membrane is suddenly made permeable to K+) is slow. This rate will decrease even more as the system goes to equilibrium. We know that the K+ current is outward, because K+ is positively charged and an outward current of positive charges makes the membrane more negative/less positive.

A strongly depolarized neuron membrane of +40 mV is far from \(\textrm{E}_{\textrm{K}^+}\), so the initial rate of diffusion of K+ (if the membrane is suddenly made permeable to K+) is rapid. This rate will decrease as the system goes to equilibrium. We know that the K+ current is outward, because K+ is positively charged and an outward current of positive charges makes the membrane more negative/less positive.

The equilibrium potential is effectively constant – ion currents don’t change this

\(\textrm{E}_{\textrm{Na}^+}\) is determined by the concentration of Na+ outside the cell relative to the concentration inside the cell ((see the Nernst equation here)https://www.physiologyweb.com/lecture_notes/resting_membrane_potential/resting_membrane_potential_nernst_equilibrium_potential.html but the details here are not part of this course) so one would reasonably think that an inward Na+ current would change this ratio (it would get smaller) and the \(\textrm{E}_{\textrm{Na}^+}\) would change (go to zero) as a consequence. It doesn’t. It takes very little ion diffusion (Na+, K+, Cl-) to drive the change in membrane potentials that we see, so the concentrations of Na+ (or K+ or Cl-) inside or outside the cell barely change. The change is small enough that we can ignore it and consider the \(\textrm{E}_{\textrm{ion}}\) to be constant.

The rising phase of the action potential is caused by an inward Na+ current; the falling phase of the action potential is caused by an outward K+ current

Voltage-gated ion channels make the axon membrane suddenly permeable to an ion

The phases of the action potential are regulated by voltage-gated ion channels. The gating mechanism of these channels is regulated by membrane voltatage. Voltage-gated Na+ channels are activated when the voltage reaches about -55 mV and are deactivated at high, positive voltages. -55 mV is the threshold potential – if the axon membrane potential rises above -55 mV, the voltage-gated Na+ channels open creating the inward Na+ current and the depolarizatiaction phase of the action potential. Voltage-gated K+ channels are activated at high, positive membrane voltages and deactived at high, negative voltages. As the action potential nears the \(\textrm{E}_{\textrm{Na}^+}\), voltage-gated K+ channels open creating a large, outward K+ current. About the same time, voltage-gated Na+ channels close. The consequence of both of these actions is a rapid repolarization of the membrane. The membrane potential moves to \(\textrm{E}_{\textrm{K}^+}\) (because the membrane is permeable to K+ only) which creates the hyperpolarization phase. This hyperpolarized membrane closes the K+ channels and the membrane potential returns to its resting (all ion equilibrium) state.

The action potential is all-or-none, meaning the magnitude of the potential (the height, or how depolarized the membrane gets) is independent of the stimulus that increases the membrane potential from it’s resting level to threshold.

There are two ways to make the membrane rise from resting level to threshold: 1) electrical activity on the dendrites – this is outlined in the next explainer, and 2) diffusion of ions along the outside and the inside of the membrane.

Action potentials propagate because of ion diffusion (“streaming”) along the outside and inside of the membrane.

An action potential travels down the membrane of the axon, so at any one time, the peak of the action potential is at a single location. We can visualize this as a reversed distribution of - and + ions, with the outside more negative than the inside. This reversal creates ion electrochemical gradients along the outside of the membrane and along the inside of the membrane. For example, along the outside of the membrane, positive ions will diffuse down their electrochemical gradient toward the location of the peak. And, along the inside of the membrane, positive ions will diffuse down there electrochemical gradient away from the peak. This creates a positive upstream current outside and a positive downstream current inside. These currents will slightly depolarize the downstream membrane (this is the small depolarization just before the depolarization phase in the image above), but enough to reach threshold and open voltage-gated Na+ channels, initiating an action potential downstream. This along-membrane diffusion creates a wave of voltage-gated Na+ channel openings that propagates toward the action terminus. This is the propagating action potential.